A fundamental issue in immunology is the fate of naive T-cells after stimulation by antigens. Accumulating data from many laboratories, including that of the principal investigator, in the last several decades have established that costimulatory signal is critical in determining whether T-cells will be activated or inactivated when the T-cell receptors are engaged by antigen. More recently, it has been shown by the principal investigator and others that costimulatory molecules also determine differentiation of T-cells after antigenic stimulation. They have demonstrated that distinct costimulatory molecules such as B7 and the heat-stable antigen (HSA) play distinct roles in the induction of two major products of T-cell response: effector and memory T-cells. The long-term goal of this research program remains to elucidate the role of multiple costimulatory molecules in T-cell activation. The current application focus on the mechanisms by which multiple costimulatory pathways participate in the induction of memory and effector CTL. First, using mice with targeted mutation of either HSA or CD28, the investigators will determine the mechanisms by which these costimulatory molecules promote the induction of memory and effector T-cells. Second, they will carry out lineage-ablation experiments to test whether effector T-cells are precursors of memory T-cells.